A rose flavor compound activating the NRF2 pathway in dendritic cells ameliorates contact hypersensitivity in mice

Abstract

Dendritic cells (DCs), which are typical antigen-presenting cells, localize to various sites in the body, particularly the front line of infection as sentinels, and are involved in innate and adaptive immune responses. Although the functions of DCs, such as pathogen-induced cytokine production and antigen-specific T cell activation, are important for host defenses against infection and tumorigenesis, the hyper- and/or extended activation of DCs leads to inflammatory and autoimmune diseases. In the present study, β-damascone, a major ingredient of rose fragrance, was selected from an aroma library as a candidate compound that suppresses antigen-induced immune responses. β-Damascone inhibited the functions of DCs, including the antigen-dependent proliferation of T cells, DC-induced Th1 development, and the TLR ligand-induced production of inflammatory cytokines by DCs. The β-damascone treatment also increased the protein level of the transcription factor NF-E2-related factor 2 (NRF2), which plays key roles in antioxidant responses, and the transcription of Hmox1 and Nqo1, target genes of NRF2, in DCs. Nrf2–/– DCs induced Th1-development and produced large amount of IL-12p40 even in the presence of β-damascone, whereas these functions by Nrf2+/– DCs were inhibited by β-damascone under the same conditions. The intake of β-damascone suppressed ear swelling in contact hypersensitivity (CHS) model mice, but not in CHS-induced Nrf2–/– mice. Collectively, the present results indicate the potential of the rose aroma compound β-damascone, which suppresses DC-mediated immune responses by activating the NRF2 pathway in DCs, for the prevention and/or attenuation of immune-mediated diseases.

The gut lactic acid bacteria metabolite, 10-oxo-cis-6,trans-11-octadecadienoic acid, suppresses inflammatory bowel disease in mice by modulating the NRF2 pathway and GPCR-signaling

“…Previous studies reported that KetoC induced the expression of the antioxidant-related genes through the activation of NRF2, in the hepatic cell line HepG2 ( 18 ), and epithelial cell line Epi4 ( 9 ). In addition, a NRF2 deficiency enhanced the expression of IL-12p40 in stimulated DCs ( 14 , 19 ). Therefore, to confirm whether γKetoC induced an antioxidant response via the activation of NRF2 in DCs, we examined NRF2 protein levels in γKetoC-treated DCs using Western blotting.…”

“…The extraction of total RNA, synthesis of cDNA, and quantitative PCR were performed as previously described ( 13 , 14 ). The nucleotide sequences of the primer sets used for qPCR are listed in Table 1 .…”

NR4A3 deficiency ameliorates contact hypersensitivity and exacerbates psoriasis by regulating gene expression in dendritic cells

“…Mice were maintained under specific pathogen-free-conditions. BMDCs were generated by cultivating BM cells supplemented with recombinant mouse GM-CSF (#576308, BioLegend) or recombinant mouse Flt3L (550706, BioLegend) as previously described 15,27,31 . The cLNs were incubated in 100 μL of RPMI-1640 containing 10 mM HEPES (pH 7.4), 50 μg/mL Liberase TL, and 200 μg/mL DNaseI for 20 min at 37 ℃ with shaking to obtain a single-cell suspension.…”

The gut lactic acid bacteria metabolite, 10-oxo-cis-6,trans-11-octadecadienoic acid, suppresses inflammatory bowel disease in mice by modulating the NRF2 pathway and GPCR-signaling

“…The extraction of total RNA, synthesis of cDNA, and quantitative PCR were performed as previously described (13, 14). The nucleotide sequences of the primer sets used for qPCR are listed in Table I.…”